Data for "Identification of a retinoic acid-dependent hemogenic endothelial progenitor from human pluripotent stem cells"

The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from hemogenic endothelium (HE) in a NOTCH and retinoic acid (RA)-dependent manner. While a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, prior to HE specification, is actually comprised of two distinct KDR+CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, while CXCR4+ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Further, both RA-independent (RAi) and -dependent (RAd) HE harbor transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human hematopoietic development provides essential resolution to the regulation and origins of the multiple waves of hematopoiesis. These insights provide the basis for the generation of specific hematopoietic populations, including the de novo specification of HSCs.